When we think of a detective the first thing that comes to mind is an investigator, either a member of a police agency or a private entity.  However there are unique detectives within the multifaceted arena of medicine.  All though we might already think of most doctors as detectives there are special doctors, units, working at the National Institute of Health’s (NIH) undiagnosed disease program.  Doctors such as William A. Gahl at the NIH are disease detectives that try to elucidate the causes and genetic basis involved in the hundreds of unsolved and mysterious diseases that arise each year.  Dr. Gahl who was interviewed for an article in scientific American explained that his group has accepted 400 out of 1700 special cases of unsolved disease.  The selection process of these cases is tough, determining which cases are new diseases and if there is a possibility of determining the genetic and biochemical basis of the disease.   As each case is worked mutations are identified that are associated with each disease.  But Dr. Gahl States that this is only the beginning of the puzzle.  The challenge becomes to identify the genetics with the pathology.

Dr. Gahls’ group has been working on a case in which a patient has endured pain for approximately twenty years and muscles of their legs have turned as hard as bricks limiting mobility.  It was determined that the patient had a rare condition in which their blood vessels bore a thick coat of calcium that restricted blood flow.  One of the first steps taken in the study was to examine the parents of the patient.  The parents after examination were healthy, which lead the group to believe that the patients’ disposition might be due to a recessive mutation.  Meaning that each parent had only one copy of a unique mutation but upon having children probability lead to the patient receiving two copies of the mutation.  After an in depth study Dr. Gahls’ group identified the location of the mutation and the error prone gene associated.  The gene that was identified is NT5E.  NT5E is involved in the production of the nucleoside adenosine (which is involved in a number of biochemical processes).  To examine this gene closely doctors cultured the patients skin cells and inserted the normal gene of NT5E and even introduced adenosine alone into the cells and miraculously they observed a reduction in calcification.  Through this analysis a better understanding of adenosine in the regulation of calcium has been brought to light.  However Dr. Gahl explains that there are a number of reasons why patients cannot just receive adenosine, but there is a class of osteoporosis drugs that pose as good candidates for treatment and they are waiting to see how these drugs perform.

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So we got into a discussion about model organisms, those that are used as a good system to be able to compare back to human beings, and in what ways they are being used.  That we have to even figure out whether or not something has a genetic basis.  Or maybe a good treatment option for a genetic disease.  If an organism shows similar symptoms as a human disease, this will give us a better understanding on when and how the disease progresses, causes and possible treatment options.

This allowed one student to immediately jump into what causes Autism.  We talked about the controversy that surrounds the disorder, and ways scientists are trying to figure out the genetic basis of the disease, and how much the environment can play a role.  In our current discussion, it was a perfect way for me to bring an actual example of how other organisms are being used to find out more about a specific disorder.

It was shown by a group of researchers at Cold Spring Harbor Laboratory that a deletion of a group of genes on chromosome number 16 causes autism-like symptoms.  They used mouse models with the same genetic alteration to show that when fewer copies of these genes are inherited, it leads to features resembling those that are used to diagnose autism.  Changes were seen in the structure of the mouse brain (see image below) and in their overall behavior of the mice.  Using the mouse model, they are able to mimic the disease to better understand what causes it, better diagnose it, and a new possible target for intervention and treatment.

Image from http://www.cshl.edu/Article-Mills/cshl-team-finds-evidence-for-the-genetic-basis-of-autism

The regions of the brain such as the hippocampus and the frontal cortex are densely populated with insulin receptors.  As well they are found in synapses in which insulin signaling participates in synaptic remodeling and synaptogenesis (1,2). In parallel insulin regulates the utilization of glucose in the hippocampus and other regions of the brain to promote optimal memory in normal metabolism (3).  In AD, it has been shown that reduced levels of insulin and insulin activity exist (4,5).  Interestingly insulin has a tight relationship to amyloid beta, a toxic peptide responsible for the onset of the disease.  Insulin can regulate the levels of amyloid beta to deliver protection from the degenerative nature of the peptide on neurons (6-8).

A pilot clinical trial published in the archives of neurology titled,  Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment, has shown insulin’ ability to be a protective new therapy in the fight against AD.  The trial hosted 104 participants, of which 30 participated in the use of a placebo, while insulin at 20IU and 40IU were delivered to 36 and 38 participants respectively.  The insulin was administered through a nasal drug delivery device for a total of 4 months. Surprisingly the 20IU and 40IU group experienced improved memory recall and preserved general cognition.

It was very important to identify a method of administration of insulin properly and direct to the brain without disrupting blood sugar levels.  When taken as a nasal spray it reaches the brain in just a few minutes with no apparent adverse affects on the body. Although a very promising study, it is still a preliminary study, more research will have to be carried out to ensure the safety and effectiveness of insulin as a therapy for longterm use against AD.

1. Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708-719. PUBMED
2. Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta. 2009;1792(5):482-496. PUBMED
3. McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. 2010;93(4):546-553. PUBMED
4. Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998;50(1):164-168. FREE FULL TEXT
5. Steen E, Terry BM, Rivera EJ; et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80. PUBMED
6. De Felice FG, Vieira MN, Bomfim TR; et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009;106(6):1971-1976. FREE FULL TEXT
7. Gasparini L, Gouras GK, Wang R; et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21(8):2561-2570. FREE FULL TEXT
8. Lee CC, Kuo YM, Huang CC, Hsu KS. Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. Neurobiol Aging. 2009;30(3):377-387. PUBMED

To find these driver mutations, scientists look for the ones that occur frequently. Until recently, this was very difficult to do. However, new sequencing technologies now let scientists look for mutations in genes at an incredible rate. The cost of sequencing is dropping dramatically; to the point where in the near future sequencing the DNA from a cancer may be sequenced as a diagnostic. Soon, it may be the cost of computing that limits our sequencing efforts.

Improvements in technology allow scientists to look at the genomes of many tumors, and there is an international effort to look at 25000 cancer genomes. This will provide the data that will let them find the mutations that lead to cancer, even if they occur in a small proportion of tumors of a particular kind. Already, hundreds of tumors have been studied in detail, which is giving scientists a good feel for the patterns of mutations that happen in cancer cells. So far, over 400 genes directly linked to cancer have been identified in this and other studies. Figuring out how these many genes contribute to cancer is likely to lead to huge advances in diagnosis and treatment, although the task remains gargantuan.

This disorder was thought to be an isolated condition, but doctors conducting follow-up studies on diagnosed patients are starting to rethink that. Anywhere from 80 to 100 percent of these RBD patients later develop neurodegenerative diseases such as Parkinson’s disease.

Doctors studying their patients conclude that there is a minimum of a 15 year difference between the onset of RBD and the onset of a neurological disorder. In some patients, the time between onsets was as much as 50 years. However long it is, this sleep disorder seems to prelude the disease by a significant amount of time. Doctors are hoping that this will allow the patient to be treated for a disease before the disease actually manifests. Perhaps one day if there is a neuroprotective treatment available, it can be used to treat these patients before the severe deterioration of their brain.

Scientists have recently identified a section of “junk” DNA that can regain function and cause disease. The section of DNA is made of repeat regions of the same sequence. They found that individuals who have 1-10 repeats on the end of chromosome 4 can develop one of the most common forms of muscular dystrophy, FSHD. The goal now is to identify a way to turn off this once non-functioning gene.

One of the important insights from the resurrection of this gene is that although some diseases can be easily explained, others result from very complicated cellular interactions. What other information will our “junk”DNA reveal in the future?

To learn more about the effects of this gene being turned on read the paper published in Science: http://www.sciencemag.org/cgi/rapidpdf/science.1189044.pdf

Well, it could be your family and it could be your environment. Studies have shown that addictions run in families. In fact, if a parent has an addiction, the child is 4 to 8 times more likely to have an addiction as well. It doesn’t necessarily have to be the same addiction, but an addiction nonetheless. Those with other family members with an addiction are more susceptible to the disease, but that also doesn’t mean that the disease is inevitable.

Saying that addiction runs in the family would speculate a possible genetic component. In fact, researchers are currently trying to link addiction to a cluster of genes in the human genome. Scientists are looking for “addiction genes” that are biologically different from others that might make someone prone to addiction. It also might affect the severity of withdrawals.

For example, in humans, a candidate gene for addiction includes the A1 allele of dopamine receptor gene DRD2 which is common in those with alcohol and cocaine addictions. Also, non-smokers are more likely to carry a protective gene, CYP2A6, which causes them to feel more nausea and dizziness from smoking.

Mice have been a model for studies on human addiction because the reward pathway functions in mice are very similar to those in the human brain.

Mice bred to lack serotonin receptor gene Htr1b are more attracted to cocaine and alcohol. Those with low levels of neuropeptide Y drink more alcohol while those with higher levels tend to abstain from alcohol.

It mainly all comes down to the reward pathway in our brains. The reward pathway is in the center of our brain and connects to other areas such as those controlling memory and behavior. It’s responsible for driving our feelings of motivation, rewards and behavior. The main job of the pathway is to make us feel good when we engage in behaviors essential to survival such as eating and drinking. Places in the brain gather information about what’s happening outside of our body and then strengthen circuits within the brain that control desirable behavior.

For instance, say you’re thirsty and someone hands you a cold water bottle. The brain will tell you that there’s cold water in front of you. Stored in your brain is a memory that says “if you drink that water, you won’t be thirsty anymore and you’ll feel good!” So you’ll drink the water. While drinking, you’re 5 senses will send a single to your brain about drinking the water. The brain, in response will release dopamine, giving you a jolt of pleasure which is your instant reward. The reward pathway will make you repeat the behavior for the same dopamine reward, like a dog doing a trick for a dog biscuit. The wiring in your brain for that particular activity has been strengthened.

Despite the genetic link, it’s not all due to our DNA makeup. Essentially, addiction is the combination of the interaction of several genes (not just a single gene) with social and environmental factors. Also, just because someone has all that’s necessary for an addiction doesn’t mean they’ll have an addiction problem. For example, I know I have an addictive personality but I look for other ways to expel or sedate the addiction and to put that addictive capability to better use.

Researchers have been searching for ways to treat and prevent addictions. One way is the identification of genes. The genes can become “drug targets,” in which researchers can work to modify the gene product’s activity resulting in stabilizing or reversing pathways to restore the brain to proper function.

Earlier this year, researchers at UT Southwestern Medical Center have a new hypothesis. They hope that by increasing a process known as neurogenesis it might prevent or treat addiction. Neurogenesis is a normally occurring process of making nerve cells in the brain. In previous studies, blocking neurogenesis had increased a rodent’s vulnerability for cocaine addiction and relapse. They hope that by stimulating the increase of neurogenesis, it might combat addiction. Another application is to use this increased neurogenesis in situations where a patient is required to use a potentially addicted medication such as Vicodin, a severe pain killer with a high addiction rate. Perhaps this treatment may be used in those who have quit their addiction in order to prevent a relapse.

Recently, new research focusing on microRNA (miRNA) and gene expression might also have a potential effect on the fight with addiction. miRNAs are used in gene expression regulation and gene silencing. They bind to complementary mRNA strands and prevent translation to a protein. Raising the levels of miR-212, an miRNA, in the brains of cocaine-using rats have caused the rodents to take in less of the drug. Completely blocking the miRNA, and allowing full gene expression, increased the drug use. This would suggest a new drug target- a medication to raise miR-212 levels or at least creating something to mimic the miRNA’s function. Liked to miR-212 is an increase in the protein CREB. CREB holds promise in fighting drug addiction by decreasing the reward response, sometimes actually creating an aversion to it all together. The only obstacle with CREB drug targets is the regulation of it. The level cannot become too low (where the rewards are increased) because it can lead to addiction and anxiety, but it cannot become too high (where nothing is rewarding) which can lead to depression. This study has only been done with cocaine and is currently under investigation for the applications in nicotine and alcohol addictions.

Someday, possibly, there will be ways for those suffering from addictions, whether they be chemical addictions, which is heavily mentioned here, or an addiction to more physical things to overcome that addiction and lead healthier lives.

Another reader wanted to know why there are cures for other diseases, but not for cancer. There are many reasons for this, of which I’ll mention a few. First, cancers are the result of our own cells acting abnormally. This means that many of the treatments we might want to use to kill cancer cells would also kill our normal cells. The challenge is to identify the differences between our normal cells and their cancerous relatives and then to identify weaknesses in the cancer cells. This in itself is very difficult. However, it is much more difficult because cancers are not all the same. As I mentioned above, cancers in different tissues arise by distinct changes, so a drug for one cancer may have no effect on another. Even worse, different cancers within a particular tissue are different. In fact, within one tumor, the different cells can have different mutations, and these can affect how the cells respond to therapy or allow the cancer to develop drug resistance. So, cancer isn’t just one disease- it is many related diseases. In fact, calling for “a cure” for cancer isn’t really fair; what will be needed are many cures for this family of diseases.

I know I’ve probably produced more questions than answers, but I hope that this helps some of you.

For example, when someone has hemophilia (a blood clotting disorder), there is a mutation in a gene that normally tells our cells how to make proteins called clotting factors. The mutation prevents a specific clotting factor from being produced, and as a result, the individual carrying the mutation has the disease and the blood doesn’t clot as it should after an injury. It’s a gene we all have, but if someone has hemophilia, the gene just isn’t working properly.

Another common misunderstanding is that if a disease is genetic, it is always inherited. It is true that many disease-causing mutations are inherited. Sometimes though, the mutations that cause genetic diseases develop over time, after we are born. Many of the mutations associated with the development of cancer, accumulate in our cells as we age, and aren’t inherited. These diseases are genetic, because they are caused by mutations in genes, but they aren’t passed from parent to offspring. Less than 10% of all cancers are inherited!

It’s no wonder that not only children, but adults too, are misinformed. These types of incorrect phrases and misinterpretations are printed all the time in magazine and newspapers. So where do you go for correct information? To learn more about the genetics of cancer, go to: www.insidecancer.org. To learn more about basic laws of inheritance, use DNA From the Beginning (www.dnaftb.org). To learn more about the inheritance of mutations that cause disease, go to: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gnd, the Online Mendelian Inheritance in Men (OMIM) database.